We have continued studies of the effects of neonatal ventral hippocampal lesions on DS-related behaviors. We have addressed the issue of genetic factors that may influence the behavioral outcome of an experimentally induced hippocampal defect. We have explored the behavioral effects of neonatal hippocampal lesions in different rat strains - Sprague-Dawley, Fischer344 and Lewis. In addition to a genetic variable, we have introduced another variable - that of the extent of the lesion (a standard lesion obtained as previously described and a small lesion obtained by infusing twice less ibotenic acid into exactly the same hippocampal location). Our results in Sprague-Dawley (SD) rats confirmed our previous findings that rats with standard neonatal excitotoxic damage do not express abnormal behavioral changes related to the mesolimbic/nigrostriatal DA system before the age of puberty, but that their responsiveness to DA-related behavioral manipulations is exaggerated after puberty. A small lesion did not produce any effects at any age. Fischer344 rats appeared to be more sensitive to the effects of the lesion. A standard lesion in these rats produced abnormal behaviors which were exaggerated in comparison with SD rats, and emerged prepubertally. A small lesion resulted in a similar pattern of changes as observed after a standard lesion in SD rats. In contrast, Lewis rats seem to be relatively resistant to the effects of the lesion. These data suggest that several factors, including a genetic program, the severity of hippocampal damage and environmental stimuli may affect the behavioral pattern associated with the early lesion. We also studied the effects of the lesion on the expression of an immediate early gene - c-fos following amphetamine challenge (10 mg/kg). We found that amphetamine increased striatal and neocortical expression of c-fos. In the medial prefrontal and parietal cortices of lesioned rats, however, this increase was significantly less pronounced than in the cortices of control rats. These data suggest that neonatal hippocampal damage affects the function of prefrontal and parietal cortices.